This paper focuses on the sustainable water quality management of the Hydro-system Danube-Tisa-Danube (HS DTD) which represents a canal network primarily constructed to provide drainage and water for irrigation, but also creates a habitat for aquatic organisms, including significant fish populations. Numerous sources of pollution both point and diffuse degrade the water quality over time, which results in eutrophication and occasional fish kills. Especially polluted is the canal reach Vrbas-Bezdan where mean annual values (period 2002-2011) for total ammonia, total phosphorus and dissolved oxygen are respectively: 6 mgNH₄/L, 1.3 mgP/L and 2.3 mgO₂/L. This paper presents a multidisciplinary approach towards the management of HS DTD’s water quality by applying an integral methodology into the management process. The methodology used involves the Geographic Information System (GIS), water quality modeling and calculating maximum permissible daily loads of nutrients. Finally, the simulation outputs are presented on the GIS maps where the observed canal reach was colour coded based on water quality levels at various points along its length. The testing done on two cases of fish kills along reaches of Vrbas-Bezdan and Bečej-Bogojevo canal could be further used within the whole canal network for achieving good water quality and supporting the fish populations.